An Effective Third Party Manufacturing Model for Speedy Technology Transfer
and Quality Oversight
Simon Hsu, Ph.D., Bristol-Myers Squibb
2014 CMC Strategy Forum
July 21-22, 2014, Gaithersburg, MD
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Outlines
• Strategic Sourcing to Korea
• Technology Transfer to Samsung Biologics
• Chemical Import Requirements in Korea
• BMS Model for Third Party Manufacturing
• BMS Technology Transfer Model
• Technical and Quality Oversight
• Conclusions
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Strategic Sourcing to Korea
Korea has well developed microbial fermentation industrial but limited track record in mammalian cell culture.
Biologics CMOs are mostly located in Songdo New City, a Free Economic Zone near Incheon.
Tax breaks, cash grants and inexpensive land
Cost advantage is about 20% – 30% over leading competitors in the West
Lower labor costs offset by the cost for global talents
Lower asset-depreciation and over-head costs
Top-notch, Europe- and US-based construction and engineering (C&E) firms for the construction of first Korean CMO facility – Celltrion
Building cost of Celltrion’s 50,000 L facility was estimated at $120 million, about 40% less than other facilities of comparable size and capacity*. * Source: “Celltrion Bringing 50,000 Liters of Cell Culture to South Korea in 2006, Triple by 2010”, 04 March 2005 21:40, ICIS Chemical Business
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BMS as a CMO Sponsor in Korea Since 2005
2005.6.21 BMS signed manufacturing agreement with Celltrion.
2007.12.18 FDA approved Celltrion to manufacture Orencia.
2013.7.18, BMS and Samsung Biologics (SBL) entered into a 10-year manufacturing agreement.
2014.4.22, BMS and SBL expanded manufacturing agreement.
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Successes from 1st Tech Transfer to SBL
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Success Key Factors
Met initial OOF date set
during kickoff : 3 ½ months
1. Good working relationship – trust, respect,
quick resolution of issues
2. BMS’s willingness to share documents,
experience, and materials necessary
3. Common goal – OOF date
Completed 8 RM co-
validation
Collaborative working relationship
Flexibility and effort by both
teams
Fair, and trusting relationship
Quick turnaround of review
and approval
1. Hard working team members
2. Common goal
3. Good working relationship
Opportunities from 1st Tech Transfer
Opportunities Improvement Areas
Last minute changes 1. Earlier discussion of process details such as
MBRs
2. More accurate document review first pass
3. Better sampling plan
4. Earlier establishment of control strategy, MBRs,
and SOPs
Urgent reviews and
approvals
1. Document approval process managed better with
more realistic dates
2. On-site technical discussion and review earlier
can reduce overall review and approval cycle
time
Delay in RM co-validation Earlier completion of RM testing requirements and
gap analysis
Earlier establishment of
Bill of Material and
procurement of RM
1. Earlier discussion of process details
2. Earlier establishment of control strategy, and
MBRs
6 A1B Nivo Kickoff Meeting April 23-24, 2014
Korean Toxic Chemical Control Act
Samples or chemicals imported to Korea need to be registered in the system of the Korean Chemical Management Association (KCMA).
To do so, the following items are required:
Information regarding the component - name, quantity, purpose of sample, manufacturer, Client personnel in charge, etc.
Packing/Commercial Invoice - stating all the components and quantities of the samples to be sent
Material Safety Data Sheet (MSDS) and Certificate of Analysis (CoA) - MSDS required for chemical registration, CoA required for material release by CMO
The Safety, Health and Environment (SHE) department of a Korean CMO will complete the chemical registration for you.
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BMS Model for Third Party Manufacturing (TPM) World Wide
BMS Biologics TPM model is based on 10 years of experience with CMOs across US, Europe, and Asia.
BMS Departments that are 100% dedicated to TPM oversight.
Biologics Third Party Manufacturing
– Project Management
– Strategic Sourcing
– Process and Analytical Specialists
Biologics TPM Quality Assurance
Staffed with individuals with prior knowledge of large scale biologics manufacturing
Matrix support from MS&T, ADT, and PD
New TPM Facility Construction
Emphasis on facility qualification and readiness for cGMP manufacture
New / inexperienced TPM
Significant investment in on-site resources to ensure success
On-site QA and/or technical offices
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Technology Transfer Model
Stage I Stage 2 Stage 3 Stage 4 Stage 5
Transfer of
Know-How
•Batch Records
•SOPs
•Flow Diagram
•Bill of Materials
•Training
•Initiate Method
Transfer
Gap
Analysis
•Facility-Fit
•Process
Adjustments
•Regulatory
Impact
Assessments
Small Scale
Test Run
•Vial Thaw
•Media
Preparation
•Cell Counting
•Inoculum
Expansion
•Column
Packing
Full Scale
Dev Run
•Upstream
•Downstream
•BDS Testing
Full Scale GMP
Campaign
•Full Scale
GMP Batches
•Product
Comparability
Tech Transfer Protocol
Approved between BMS and TPM at the onset of tech transfer
Defined Teams and Responsibilities
Steering Team Committee
Joint Steering Committee
Quality Council
Quality Agreement
Legal Contract (Supply Agreement)
Supply Chain Management
Go/No-Go Decisions in Each Stage of Technology Transfer
Technical Team
Training of Process Know-How
Facility Fit Analysis
Process Performance Analysis and Recommendation
Analytical Testing Method Transfer
QA People in the Plant (QA PIP) Implementation of QA PIP
Full time presence at the TPM, including time between campaigns
Factors which influence decision to hire QA PIP
– Commercial manufacture
– New facilities
– 30+ lots per year
– Long geographical distance (e.g. Asia)
Staffing:
– 1 Manager (release authority)
– 1-3 QA Specialists used for batch review
QA PIP Activities
Follow BMS SOPs specific for QA oversight of TPM activities
Review and approval of: batch records, change controls, deviations
On-site drug substance disposition
On the floor presence for troubleshooting
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Technical Subject Matter Experts (SMEs)
Technical SMEs located at the TPM for initial scale-up / GMP runs and process validation campaigns
On-the-floor coverage for all manufacturing shifts
– Ensure process performed correctly
– Real-time trouble shooting
Analytical SME’s present to monitor release testing of first GMP lot
Successful campaigns at TPM results in on-time IND/BLA submissions
Routine production: BMS SME’s frequently at the TPM for select activities
Column packing
First few lots of manufacturing campaign
Troubleshooting manufacturing and analytical issues
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Current BMS PIP Model
Proactive approach
Pre-campaign readiness meetings and gap analysis
Facility and equipment walk through to ensure facility fit and equipment readiness
Set expectations with CMO
PIP trained at the process donor site
Phase-based approach
Full-time PIP coverage during initial tech transfer and critical campaigns such as PPQ and PAI.
Multiple functional coverage during technology transfer and PPQ until the manufacturing process is proven robust.
Site-based approach
On-the-floor coverage depends on proximity and consistent performance of CMOs
Quality/Technical offices have been set up for CMOs in Asia and Europe
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Conclusions
Sourcing to Korea increases our biologics manufacturing capability and gives us the flexibility to respond to global needs of patients
Sourcing to Korean CMOs can be successful if you have the experience and necessary resources
Sponsor or License holder assumes overall and final responsibility for the product made at the CMO
Successful quality oversight of CMO can only be achieved by an effective, integrated cross-functional team
On-site quality/technical office is an integral part of BMS CMO oversight worldwide
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